Bruce E. Herring - US grants

DESCRIPTION (provided by applicant): The overall goal of this research program is to better understand the role of kalirin-7 in excitatory synaptic transmission and plasticity and how disruption of the function of this protein might be involved in complex neuropsychiatric disorders such as schizophrenia and Alzheimer's disease. The applicant for this K99/R00 Pathway to Independence Award, Dr. Bruce Herring, is a postdoctoral fellow with Dr. Roger Nicoll at UCSF. Dr. Herring's long-term career goal is to lead an independent research laboratory in basic neuroscience research as a tenure-track principle investigator in an academic research institution. Dr. Herring's long-term research goal is to use a combination of cellular, molecular, electrophysiological, imaging, biochemical and genetic approaches to elucidate the cellular and synaptic level mechanisms that govern synaptic transmission, underlie synaptic plasticity and give rise to neuropsychiatric disease. Though etiological mechanisms underlying schizophrenia remain largely unknown, a convergence of pharmacologic, genetic and morphological data implicates a dysregulation of spine stability, excitatory transmission and synaptic plasticity in tis disease. Kalirin-7 has been shown to have a critical role in spino- and synaptogenesis and maintenance, is regulated by DISC1, a protein heavily implicated in schizophrenia, and several mutations in the KALRN gene have been identified as possible genetic risk factors for this disease. Furthermore, phosphorylation of an N-terminal threonine residue (T95) by CaMKII augments kalirin-7's ability to activate small GTPases that are involved in regulating synapse morphology. CaMKII is critical in the induction of long-term potentiation (LTP), a phenomenon thought to be one of the primary mechanisms underlying synaptic plasticity and generally regarded as the cellular basis of learning and memory. However, the targets of CaMKII phosphorylation responsible for giving rise to LTP have not been identified. Given kalirin-7's potential role in LTP, coupled with the implication of this protein in dendritic spine maintenance and a number of neuropsychiatric diseases, may indicate that kalirin-7 represents a key point of convergence between the molecular mechanisms underlying learning, memory and neuropsychiatric disorders. Using a combination of innovative genetic approaches allowing endogenous kalirin to be replaced with recombinant kalirin-7 mutants in individual neurons, Dr. Herring proposes a systematic investigation into the role of kalirin-7 phosphorylation by CaMKII in excitatory synaptic morphology, function and learning and memory. By combining his training in molecular and cellular biology, pharmacology and synaptic electrophysiology, Dr. Herring will pursue additional training in imaging and biochemical methods to address the following specific aims: 1) Determine the role kalirin-7 phosphorylation plays in the regulation of excitatory synapses, learning and memory; 2) Identify whether kalirin-7 and Trio represent redundant pathways supporting LTP; 3) Identify functionally relevant protein-protein interactions involving kalirin-7. Successful completion of this application will identify new mechanisms and new proteins underlying and modulating LTP and will open new frontiers for the development of disease-modifying therapeutic approaches for schizophrenia and other neuropsychiatric disorders. Furthermore, the training period afforded by the K99/R00 Award will provide Dr. Herring with a powerful toolbox for his independent career investigating the molecular mechanisms underlying synaptic transmission, plasticity and disease.

Program Director/Principal Investigator (Last, First, Middle): Herring, Bruce, E. PROJECT SUMMARY Autism Spectrum Disorder (ASD) is a leading cause of mental impairment for which there is no known cure. Mounting evidence points to a convergence on altered actin-mediated regulation of postsynaptic glutamatergic synaptic function as a basis for ASD. We have recently identified an unprecedented clustering of ASD-related mutations in the GEF1 domain of the synaptic actin regulatory protein, Trio, that results in a strong genome-wide statistical association of the TRIO gene with ASD. The long-term goal of our research is to identify core synaptic regulatory machinery onto which numerous ASD causing factors converge. Identification of synaptic ?convergence points? of ASD-risk genes will help simplify the genetic landscape of this disorder and thus, aid in the development of new strategies to treat individuals with a diverse array of ASD-causing factors. Our central hypothesis is that ASD mutations in Trio disrupt a multitude of synaptic regulatory pathways, and that disruption of these pathways results in glutamatergic synapse dysfunction that contributes to the development of ASD- related behavioral phenotypes. Guided by strong preliminary data we will pursue this hypothesis in three specific aims. In Aim 1, we will combine proteomic, biochemical, electrophysiological, and super-resolution imaging techniques to identify novel synaptic regulatory mechanisms involving Trio. In Aim 2, we will combine these same approaches with computational modeling to reveal Trio-related synaptic regulatory mechanisms disrupted by Autism-related mutations and provide a comprehensive picture of the synaptic disruption that results from Autism-specific Trio dysfunction. And, for Aim 3, we have engineered a conditional knock-in mouse that allows CRE-dependent expression of an ASD-related mutant form of Trio. Using this new and powerful genetic tool, we will conduct a battery of behavioral tests to assess the impact of ASD-related Trio mutations on mammalian behavior. Growing evidence now suggests that neurological sensory processing deficits underlie the development of many common ASD-related behavioral phenotypes. Because of this, we propose the use of state-of-the-art techniques that allow careful examination of somatosensory processing in these mice. The present proposal is innovative because it assembles a team of collaborators with diverse areas of expertise and deploys new and powerful genetic tools that will allow a multi-dimensional approach to understanding how disruption of synaptic function leads to ASD. The proposal is significant because it stands to identify an important synaptic signaling hub that links numerous synaptic proteins previously implicated in ASD and will vertically advance our understanding of ASD from synapse to circuit to behavior. This proposal squarely meets the mission objectives of the NINDS given its focus on how synaptic dysfunction ultimately leads to key neurological deficits that likely underlie many core behavioral phenotypes associated with ASD. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Continuation Format Page